Field of the Invention
The present invention relates to the field of medicine. More specifically, the invention relates to compositions containing cerium oxide nanoparticles for the treatment and prevention of stroke and cardiovascular disease.
Description of the Related Art
Many approaches have been taken to treat, either therapeutically or prophylactically, diseases, disorders, and other medically important conditions that have, as a major component, cell injury or death due to free radicals, such as oxygen radicals. Among those approaches were the use of free radical scavengers, such as Vitamin E and its related compounds, Vitamin C and its related compounds, and melatonin, to name a few. While the beneficial effects of these compounds have been noted, researchers and clinicians continue to search for compounds with higher activities and half-lives.
In early experiments performed by the present inventors and their colleagues, cerium oxide nanoparticles prepared by a sol-gel process were utilized to enhance cell longevity. The cerium oxide nanoparticles were proposed to act as free radical scavengers to bring about the observed results. However, the sol-gel process posed several difficulties. For example, particle size was not well-controlled within the reported 2-10 nm range, making variability between batches high. That is, the process, while satisfactory for producing nanoparticles with free radical scavenging activity, did not reproducibly produce particles of a specific size range. Thus, each batch of particles needed to be tested to confirm the size range and the suitability of the batch for use. In addition, the process resulted in tailing of surfactants used in the process into the final product. The presence of these surfactants produced biological difficulties when used, primarily due to the toxicity of the surfactants in the product. Furthermore, the inability to control the amount of surfactant tailing posed problems with agglomeration when nanoparticles were placed in biological media. These difficulties reduced particle efficacy and biological deliverability. Removal of surfactant after sol-gel synthesis produced particles that appeared prone to agglomeration in biological media, and had a lack of biological effects. Further, difficulties were encountered with changes in valence state of cerium associated with these particles, causing alterations in the ratio of valence states of cerium (+3/+4) that occurred over time, particularly when particles were placed in biological media. It is possible that the +3/+4 ratio of valence states in the nanoparticles might alter free radical scavenging and cellular delivery, including delivery in vivo.
Damage from ischemic stroke results from generation of free radicals in neurons and other brain cells, which cause in cellular demise and loss of function. Loss of energy production due to damaged mitochondria is also evident. Depending on the size and location of the stroke, functional deficits can range from mild loss of coordination and limb movement to coma.
It has been shown that cerium oxide nanoparticles (CeONP) are potent and effective regenerative free radical scavengers and mitochondrial protectants (Bailey et al., Nature Biotechnology 14, 112 (2003); Rzigalinski et al., Nanomedicine, 1: 399-412 (2006); Rzigalinski et al., Antioxidant Nanoparticles in Nanomedicine in Health and Disease, Science Publishers, 2012). It has also been shown that CeONP show promise in treatment of traumatic brain injury (Whiting et al., J. Neurotrauma 26, 101 (2009)) and Parkinson's Disease (Dillon et al., “Cerium oxide nanoparticles protect against MPTP-induced dopaminergic neurodegeneration in a mouse model for Parkinson's Disease” Proc. of International Conf. on Nanotechnology, in press), and other neurodegenerative disorders. However, the use of cerium oxide nanoparticles for the treatment of stroke has not been previously demonstrated.